Polyhydronaphthalene lactone compound and a process of making same



The present invention relates to a new polyhydronaphthalene lactone compound and, more particularly, to the lactone of 5;.8 hydroxy-8-oxo-l,4,4au,5,8,8aahexahydronaphthalenelfi-carboxylic acid and a process of making same. Woodward et al. described in J. Am. Chem. Soc., vol. 78, page 2023 (1956), a total synthesis of reserpine. Said alkaloid is used in therapy for the treatment of hypertension and certain mental diseases. Recently, Woodward et al. described a variation of the above mentioned synthesis in I. Am. Chem. Soc., vol. 78, page 2657 (1956). This variation does not require as many steps as the first m ntioned process of Woodward et al. According to said variation, th hydroxy lactone of Permitla 1' is used-as an intermediate.

It is one object of the present invention to provide a simple and effective process of producing said 1,8-lactone of 5,6,8B-dihydroxy-1,4,4au,5,8,8aa-hexahydronaphthalene-lB-carboxylic acid of Formula I by using Sp-hydroxy-8-oxo-1,4,4aa,5,8,8aa-hexahydronaphthalene 118- of Formula II is obtained according to the present invention by subjecting 5,8-hydroxy-8-oxo-1,4,4aa,5,8,8aet-hexahydronaphthalene-lfl-carboxyl acid of F ormula III U te strew -t o 2,931,815 Fatented Apr. 5, 1960 ice o coon to the action of a lactonizing agent and, preferably, to the action of aceticacid anhydride in the presence of sodium acetate in dichloro ethane. The compound of Formula III is readily produced by condensing vinyl acrylic acid and p-benzoquinone and reducing the reaction product by means of sodium boron hydride.

The new lactone of Sfi-hYdI'OXY-S-OXO-1,4,4aa,5,8,8at?!f hexahydronaphthalene-lfl-carboxylic acid of Formula II is readily converted into the 1,8'lactone of 5p,8,3 -dihy-' droxy-1,4,4aot,5,8,8aot-hexahydronaphthalene -1,8- carboxylic acid of Formula I by reduction by means of aluminum isopropylate.

Although the process of preparing reserpine according to Woodward et a1. as described in I. Am. Chem. Soc. 78, p. 2657 (1956), requires fewer steps than the process using the intermediate steps of the present invention, said new process has the great advantage that it permits preparation of the hydroxy lactone of Formula II on a large scale and without difficulty. This is due to the following facts. Vinyl acrylic acid is more readily avail able than the corresponding methyl ester used in the Woodward et al. method. Furthermore, vinyl acrylic acid reacts with p-benzoquinone with a better yield than its methyl ester. The methyl ester of vinyl acrylic acid requires preliminary preparation of the methyl ester of malonic acid.

L'actonization of the hydroxy carboxylic acid of Fai mula III to the lactone of Formula II proceeds in acid medium with an excellent yield. A further advantage of the process according to the present invention consists in the ease with which the lactone of Formula II can be reduced to the lactone of Formula I'as has been stated above by means of aluminum isopropylate.

In contrast thereto, reduction of the methyl ester of the condensation product of vinyl acrylic acid methyl ester and p-benzoquinone of Formula IV I O COOCH;

by means of aluminum isopropylate to form the hydroxy lactone of Formula I is always accompanied by simultaneous saponification and lactonization. As a result thereof the total yield is not very high.

In order to produce the new lactone of 5,3-hydroxy-8- oxo-1,4,4aa,5,8,8aa-hexahydronaphthalene -1ficarboxylic acid of Formula II, 5,8-hydr0xy-8-oxo-1,4,4aa,5,8,8au=- hexahydronaphthalene-IB-carboxylic acid of Formula III is heated with an excess of acetic acid anhydride in the presence of sodium acetate at a temperature between about C. and about 100 C. and, preferably, at about C. Lactonization is efiected in the presence of an inert solvent such as benzene or ethyl acetate or, preferably, a chlorinated solvent such as dichloro ethane. After lactonization is completed, the reaction mixture is I I H neutralized by the addition of sodium bicarbonate and is 0 evaporated to dryness.

droxy-8-oxo -1,4,4E10t,5,8,830thexahydronaphthalene 148-.

carboxylic acid is obtained in an almost quantitative yield. After recrystallization, the yield of the pure lactone exceeds 80% of the theoreticalyield.

The following example serves-to illustrate the present invention without, however, limiting the same thereto. In particular, other solvents may be used and the reaction temperature may be varied in accordance with the principles set forth herein and in the claims annexed thereto. The melting points are points of instantaneous melting. They are determined on the Maquenne block.

EXAMPLE Preparation of the lactone of fi-hydroxy-8-oxo-I,4,4a, 5,8,8aa hexahydronaphthalene lfl carboxylic acid (Formula II) 900 cc. of dichloro ethane, 400 cc. of acetic acid anhydride, and 100 g. of sodium acetate are heated at 60- 65 C. with stirring for 15 minutes. 200 g. of S B-hydroxy 8 oxo 1,4,4aa,5,8,8aa hexahydronaphthalenelfi-carboxylic acid of Formula 111 are added at once. The acid dissolves rapidly. The solution turns yellow. It is heated under reflux for 15 minutes, cooled to 20 C. with stirring, and poured into water without discontinuing stirring. 600 g. of sodium bicarbonate are added to the mixture. Stirring is continued for several hours. The mixture is allowed to stand overnight. The dichloro ethane layer is separated by decanting, washed with 500 cc. of a saturated aqueous sodium bicarbonate solution, again decanted, and washed with water. The Wash waters are combined with the aqueous layer of the reaction mixture. They are again extracted twice with dichloro ethane. The extracts are washed with sodium bicarbonate solution and with water. All the dichloro ethane extracts are combined, dried over sodium sulfate, filtered, treated with charcoal, and evaporated to dryness. The residue which is the desired crystalline lactone compound of Formula II is freed from adhering dichloro ethene by the addition of and distillation with ethyl acetate. The residue is mixed with ethyl acetate to form a paste while heating. The paste is then cooled. After drying, 151 g. (83% of the theoretical amount) of the desired lactone compound of Formula II are obtained. The

compound forms colorless crystals and melts at 150 C. It is insoluble in water and, ether and slightly soluble in methanol, ethanol, and ethyl acetate.

Analysis: C I- 0 :1902 Calculated-69.46% C; 5.3% H; 25.24% O.'- Found-69.5% C; 5.4% H; 25.6% 0. I H

This compound is not described in the literature.

As stated above, this lactone of 5B-hydroxy-8-oxo-1A, 4au,5,8,8aa-hexahydronaphthalene-lfl-carboxylic acid of Formula II is readily converted by heating under reflux in isopropyl alcohol with aluminum isopropylate into' the 1,8-lactone. of 518,8;8-dihydroxy-l,4,4aa,5,8,8aa-hexahydronaphthalene-lp-carboxylic acid of Formula 1. Further conversion'of said 1,8-lactone into reserpine is carried out by following the procedure described by Woodward et al. (l.c.). 1

We claim:

1. The lactone of 5B-hydroxy-8-oxo-1,4,4aot,5,8,8ahexahydronaphthalene-lfl-carboxylic acid of the formula 2. The process of preparing the lactone of SB-hydroxy- 8 oxo 1,4,43a,5,8,8au hexahydronaphthalene 1 8- carboxylic acid which comprises heating SB-hydroxy-S- oxo 1,4,4aa,5,8,8aa hexahydronaphthalene lit-carboxylic acid with an excess of acetic acid anhydride in the presence'of sodium acetate and with the addition of a solvent at a temperature between about C. and about 100 C. until lactonization is completed.

3. The process according to claim 2, wherein the solvent is a solvent selected from the group consisting of dichloro ethane, benzene, and ethyl acetate.

4. The process according to claim 2, wherein the lactonization reaction temperature is about C.

References Cited in the file of this patent Woodward et al.: J. Am. Chem. Soc., vol. 78, pp. 2023-4 (1956). 

1. THE LACTONE OF 5B-HYDROXY-8-OXO-1,4,4AA,5,8,8AAHEXAHYDRONAPHTHALENE-1B-CARBOXYLIC ACID OF THE FORMULA 